EP0288563B1 - Derives d'amines cycliques - Google Patents

Derives d'amines cycliques Download PDF

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Publication number
EP0288563B1
EP0288563B1 EP86905925A EP86905925A EP0288563B1 EP 0288563 B1 EP0288563 B1 EP 0288563B1 EP 86905925 A EP86905925 A EP 86905925A EP 86905925 A EP86905925 A EP 86905925A EP 0288563 B1 EP0288563 B1 EP 0288563B1
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Prior art keywords
cyclic amine
compound
general formula
formula
acceptable salt
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German (de)
English (en)
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EP0288563A1 (fr
EP0288563A4 (en
Inventor
Hachiro Sugimoto
Takaharu Nakamura
Norio Karibe
Isao Saito
Kunizo Higurashi
Masahiro Yonaga
Takeru Kaneko
Takahiro Nakazawa
Masataka Ueno
Kiyomi Yamatsu
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Eisai Co Ltd
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Eisai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to cyclic amine derivatives having excellent medicinal activities.
  • cerebral vasodilator drugs and cerebral metabolism activators have been used.
  • no drug which is drastically effective has been proposed as yet.
  • an object of the present invention is to provide cyclic amine derivatives and pharmacologically acceptable salts thereof which are effective for the treatment of cerebral vascular disorders such as cerebral stroke, apoplexy, infarction and arteriosclerosis and mental symptoms due to multiple infarct dementia.
  • Another object of the invention is to provide a process for producing said compounds or pharmacologically acceptable salts thereof.
  • Still another object of the invention is to provide medicines containing said compound or pharmacologically acceptable salt thereof as the active ingredient.
  • the lower alkyl groups in the above-mentioned definitions of R1 and B include, for example, straight-chain or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. Among them, methyl and ethyl groups are the most preferred.
  • the lower alkoxy groups in the above-mentioned definition of B are those derived from the above-mentioned lower alkyl groups. Preferred examples of them include methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy groups.
  • substituents of the "substituted or unsubstituted phenyl group” and “substituted or unsubstituted naphthyl group” in the definition of A include, for example, the above-defined lower alkyl and alkoxy groups, hydroxyl group, halogen atoms such as fluorine, bromine, iodine and chlorine, phenyl group and heterocyclic groups having nitrogen atom(s) as the hetero atom such as imidazolyl, pyridyl and pyrazolyl groups. Said compounds may have one to three of these substituents. When the compound have two or more of these substituents, they may be the same or different.
  • the phenyl group may have a methylenedioxy or ethylenedioxy group bonded with two different carbon atoms constituting the phenyl ring in addition to the above-mentioned substituents.
  • the substituted phenyl group include also a group of the formula:
  • the acyl groups in the definition of R1 include organic acid residues such as saturated aliphatic, unsaturated aliphatic, carbocyclic and heterocyclic carboxylic acid residues.
  • Examples of them include lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups, aroyl groups such as benzoyl, toluoyl and naphthoyl groups and heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups.
  • lower alkanoyl groups such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloyl groups
  • aroyl groups such as benzoyl, toluoyl and naphthoyl groups
  • heteroaroyl groups such as furoyl, nicotinoyl and isonicotinoyl groups.
  • the arylalkyl groups in the definition of R1 include, for example, those derived from substituted or unsubstituted phenyl and naphthyl groups. Typical examples of them include benzyl and phenethyl groups.
  • the substituents in the above definition include, for example, the above-defined lower alkyl and lower alkoxy groups, hydroxyl group and halogen atoms such as fluorine, bromine, iodine and chlorine atoms.
  • heteroarylalkyl groups include pyridylalkyl groups such as picolyl group.
  • the halogen atoms include fluorine, chlorine, bromine and iodine atoms.
  • the phamacologically acceptable salts are ordinary non-toxic salts, for example, inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and amino acid salts such as arginine salts, aspartates and glutamates.
  • inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates
  • organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates
  • amino acid salts such as arginine salts, aspartates and glutamates.
  • the compounds of the present invention can be produced by various processes.
  • a typical example of these processes comprises: wherein Hal represents a halogen atom and A, X, Y, Z, B, n , m and are as defined above.
  • the dehydrohalogenation reaction is carried out by heating in an ordinary manner without using any solvent or in an organic solvent inert to the reaction which is selected from the group consisting of alcoholic solvents such as methanol, ethanol and butanol, benzene, toluene, xylene, tetrahydrofuran, chloroform, carbon tetrachloride and dimethylformamide.
  • alcoholic solvents such as methanol, ethanol and butanol
  • Preferred results are obtained when the reaction is carried out in the presence of an inorganic salt such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate or sodium hydroxide or an organic base such as triethylamine, pyridine, pyrimidine or diethylaniline.
  • the compounds of the present invention have excellent pharmacological effects on the central nervous system, particularly a remarkable reparative effect on ischemic cerebral vascular disorders. Therefore, these compounds are useful for relieving, remedying or preventing mental disorders due to the cerebral vascular disorders such as cerebral stroke, apoplexy, infarction, arteriosclerosis and dementias, e.g. multiple infarct dementia.
  • LD50 of them was 2,000 to 4,000 mg/kg (oral administration to rats).
  • the compounds of the present invention used as the medicine are given either orally or parenterally.
  • the dose of said compounds is not particularly limited, since it varies depending on the symptoms; age, sex, body weight and sensitivity of the patient; period and intervals of the administration; properties, composition and kind of the medicinal preparation; and varieties of active ingredients.
  • about 0.1 to 300 mg/day, preferably about 1 to 100 mg/day of the compound is administered 1 to 4 times a day.
  • the compounds of the present invention are used in the form of a medicinal preparation such as an injection, suppository, sublingual tablet, tablet or capsule.
  • a pH adjustor, buffer, suspending agent, solubilizer, stabilizer, isotonizer, preservative, etc. are added to the active ingredient to form an intravenous, subcutaneous or intramuscular injection by an ordinary method. If necessary, the injection can be freeze-dried by an ordinary method.
  • suspending agents examples include methylcellulose, Polysorvate 80, hydroxyethylcellulose, acacia, tragacanth gum powder, sodium carboxymethylcellulose and polyoxyethylenesorbitan monolaurate.
  • solubilizers examples include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol and ethyl esters of castor oil fatty acids.
  • Examples of the stabilizers include sodium sulfite, sodium metasulfite and ether.
  • Examples of the preservatives include methyl hydroxybenzoate, ethyl hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
  • mice Carotid arteries of both sides of ICR mice (6 to 8 weeks old) were exposed under halothane anesthesia and ligated. The mice thus treated had stroke symptoms such as jumping, rolling and convulsion and almost all of them died within 24 h.
  • the compound of the present invention was administered orally to the mice one hour before the ligation and the survival time (maximum: 6 h) was examined as an index of the effect of protecting eschemic brain.
  • the compound was used in the form of a 5% suspension in acacia and a 5% acacia solution was given to the control group.
  • the learning and memory functions were examined by the passive avoidance method with a modification of a device reported by Jarvik & Kopp in "Psychological Reports", 21 , 221 to 224 (1967).
  • the device had two chambers, i.e. a well-lighted chamber A and a dark chamber B.
  • an electric current (A.C., 1.6 mA) was applied to a grid on the floor of the dark chamber B for 5 min when they entered the chamber B.
  • the animals subjected to the learning were placed in the chamber A and the time (latent time) which had elapsed before they entered the chamber B was measured.
  • the upper limit of the latent time was set at 300 sec.
  • the compound was administered in the form of a 5% suspension in acacia orally one hour before causing the ischemia.
  • a 5% acacia solution was administered to the control group.
  • the results are shown in Table 3.
  • the average latent time of the normal (pseudo-operation) group was 246.5 sec and that of the control group was as short as 71.5 sec. Namely, the learning and memory functions of them were damaged by the 5-min ischemia.
  • the latent time was elongated again, namely the learning disorder after the ischemia was remedied.
  • the compound of the present invention was administered orally to them, while a 5% acacia suspension was administered to the control group. After one hour, the ischemia was realized for 5 min. After one week, the animal was perfused and fixed with 4% neutral formalin transcardially. The treated sample was embedded in paraffin and cut to obtain slices having a thickness of 3 ⁇ m. The slices were dyed with hematoxylin-eosin and the number of the nerve cells in the CAI region of the hippocampus of each slice was counted.
  • the results are shown in Table 4.
  • the nerve cell density in the CAI region of the hippocampus was 287/mm in the normal (pseudo-operation) group and that of the control group was as small as 21/mm. Namely, a serious disappearance of the cell was caused by the 5-min ischemia.
  • the nerve cell density was increased to prove the effect thereof in protecting the cells from the disorder.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Treating Waste Gases (AREA)
  • Lubricants (AREA)
  • Steroid Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Claims (6)

  1. Dérivés d'amines cycliques, ou sels pharmacologiquement acceptables de ceux-ci, de formule générale :
    Figure imgb0053
     dans laquelle A est un groupe naphtyle ou naphtyle ayant un substituant choisi parmi un halogène et un groupe alkyle en C₁ à C₆ ;
    X est -CO- ou -CH(OH)- ;
    n vaut 0 à 4 et
    B est un groupe phényle ou phényle ayant un substituant choisi parmi un halogène et un groupe alkyle en C₁ à C₆.
  2. Dérivé d'amine cyclique ou sel pharmacologiquement acceptable de celui-ci selon la revendication 1 répondant à la formule
    Figure imgb0054
     qui est la 2-[4-(p-fluorobenzoyl)-1-pipéridinyl)-2-acétonaphtone.
  3. Dérivé d'amine cyclique ou sel pharmaceutiquement acceptable d'un composé de formule :
    Figure imgb0055
     qui est le 2-[4-(p-fluorobenzoyl)-1-pipéridinyl]-1-naphtyléthanol.
  4. Procédé pour préparer un dérivé d'amine cyclique répondant à la formule de la revendication 1, caractérisé par la réaction d'un halogénure de formule générale
    Figure imgb0056
     dans laquelle Hal représente un atome d'halogène et A, X et n sont définis comme précédemment, avec un composé de formule générale
    Figure imgb0057
     dans laquelle B est défini comme précédemment, pour former un dérivé d'amine cyclique répondant à la formule générale de la revendication 1 et, si nécessaire, la conversion de ce composé en un de ses sels pharmacologiquement acceptables.
  5. Médicament pour le soulagement, la guérison ou la prévention des symptômes mentaux dus aux troubles cérébro-vasculaires, qui contient comme ingrédient actif un dérivé d'amine cyclique répondant à la formule générale de la revendication 1 ou un sel pharmacologiquement acceptable de celui-ci.
  6. Utilisation d'un composé répondant à la formule générale de la revendication 1 ou d'un sel pharmacologiquement acceptable de celui-ci pour la préparation d'un médicament pour le soulagement, la guérison ou la prévention des symptômes mentaux dus à des troubles cérébro-vasculaires.
EP86905925A 1986-09-30 1986-09-30 Derives d'amines cycliques Expired - Lifetime EP0288563B1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP1986/000502 WO1988002365A1 (fr) 1986-09-30 1986-09-30 Derives d'amines cycliques

Publications (3)

Publication Number Publication Date
EP0288563A1 EP0288563A1 (fr) 1988-11-02
EP0288563A4 EP0288563A4 (en) 1990-09-26
EP0288563B1 true EP0288563B1 (fr) 1994-05-11

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Country Status (9)

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EP (1) EP0288563B1 (fr)
KR (2) KR910006138B1 (fr)
AT (1) ATE105550T1 (fr)
AU (1) AU599339B2 (fr)
DE (1) DE3689836T2 (fr)
DK (1) DK273788D0 (fr)
FI (1) FI90533C (fr)
NO (1) NO175055B (fr)
WO (1) WO1988002365A1 (fr)

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US8088782B2 (en) 2008-05-13 2012-01-03 Astrazeneca Ab Crystalline 4-(3-chloro-2-fluoroanilino)-7 methoxy-6-{[1-(N-methylcarbamoylmethyl)piperidin-4-yl]oxy}quinazoline difumarate form A
US8604031B2 (en) 2006-05-18 2013-12-10 Mannkind Corporation Intracellular kinase inhibitors

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ES2043557B1 (es) * 1992-06-04 1994-07-01 Ferrer Int Procedimiento de obtencion de nuevos derivados de la 4-bencilpiperidina.
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AU599339B2 (en) 1990-07-19
NO882372L (no) 1988-05-30
KR910006138B1 (ko) 1991-08-16
KR880701710A (ko) 1988-11-04
DK273788A (da) 1988-05-19
EP0288563A1 (fr) 1988-11-02
NO175055C (fr) 1994-08-24
FI90533B (fi) 1993-11-15
FI90533C (fi) 1994-02-25
DK273788D0 (da) 1988-05-19
EP0288563A4 (en) 1990-09-26
DE3689836T2 (de) 1994-09-22
FI882369A (fi) 1988-05-19
AU6405486A (en) 1988-04-21
WO1988002365A1 (fr) 1988-04-07
NO175055B (no) 1994-05-16
DE3689836D1 (de) 1994-06-16
ATE105550T1 (de) 1994-05-15
NO882372D0 (no) 1988-05-30
FI882369A0 (fi) 1988-05-19

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